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Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp. 1665-1669 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.7637 Phase II Trial of Infusional Fluorouracil, Leucovorin, Mitomycin, and Dipyridamole in Locally Advanced Unresectable Pancreatic Adenocarcinoma: SWOG S9700
From the University of California, Los Angeles Medical Center, Los Angeles, CA; Southwest Oncology Group Statistical Center, Seattle, WA; University of Cincinnati Medical Center, Cincinnati, OH; St Vincent's Cancer Care Center, New York, NY; and Karmanos Cancer Institute, Wayne Sate University, Detroit, MI Address reprint requests to Philip A. Philip, MD, PhD, FRCP, Karmanos Cancer Center, 4-HWCRC, 4100 John R St, Detroit, MI 48201; e-mail: philipp{at}karmanos.org
Purpose To test the hypothesis that dual biochemical modulation of fluorouracil (FU) in combination with mitomycin improves the survival of patients with pancreas cancer. Patients and Methods Eligibility included stage II or III unresectable adenocarcinoma of the pancreas, performance status of 0 to 2, and adequate organ function. Treatment included FU 200 mg/m2/d via continuous intravenous infusion for 4 weeks followed by 1 week of rest; leucovorin 30 mg/m2 administered via intravenous bolus infusion on days 1, 8, 15, and 22, followed by 1 week rest; mitomycin 10 mg/m2 intravenous bolus infusion every 6 weeks for a total of four doses. Dipyridamole 75 mg was administered orally three times daily during the FU administration. Results Fifty patients (median age, 61 years; 23 males, 27 females) with localized unresectable pancreatic cancer were eligible for this trial. Twenty-seven patients survived past 1 year for a 1-year survival probability of 54% (95% CI, 40% to 68%). Overall, the objective response rate was 26% (confirmed and unconfirmed) in the 47 patients with measurable disease, with two complete responders. Six of the responding patients underwent curative successful resection of the tumor. The most common toxicity to treatment was stomatitis. Three patients had reversible hemolytic uremic syndrome. Five patients experienced grade 4 toxicity. There were no treatment-related deaths. Conclusion Potential improvement in survival and resectability of localized unresectable pancreatic cancer may be attained without radiation. The strategy of dual biochemical modulation of FU warrants additional investigation in a randomized fashion.
Pancreatic cancer is the fourth leading cause of cancer-related death within the United States. Fewer than 5% of patients with pancreatic cancer are alive at 5 years.1,2 Surgery offers the only possibility for cure but only 20% of carefully screened patients undergo curative resection. Approximately 40% of patients with pancreatic cancer present with locally advanced unresectable disease.3 Historically, these patients have received radiation plus fluorouracil (FU), per the results of initial trials of the Gastrointestinal Tumor Study Group.4 In the patients who received either the low-dose radiation alone or high-dose radiation plus FU, the median survival was 42.2 and 40.3 weeks, respectively. For the radiation-alone arm, the median survival was only 22.9 weeks. Subsequent studies tested the utility of combination chemotherapy plus radiation, chemotherapy alone (single agent or combination), or radiation alone.5-9 These regimens added little to the quality of life or survival; no therapeutic regimen was proven to be more effective than radiation plus FU. Empiric combination chemotherapies based on FU or gemcitabine have met no major successes in treating patients with advanced disease. Attempts to improve the therapeutic effects of FU have included biochemical modulation and adding other chemotherapeutic agents.10 Fluorodeoxyuridine monophosphate (an active metabolite of FU) binds to the enzyme thymidylate synthase, preventing the conversion of deoxyuridine monophosphate to thymidylate, the precursor to thymidine triphosphate (dTTP), which is one of the four essential nucleotides required for DNA synthesis and repair.11 Continuous infusion of FU causes a more sustained depletion of dTTP, enhancing its anti-DNA effect.12-15 Thymidine kinase converts intracellular thymidine to thymidine monophosphate, which is further phosphorylated to the triphosphate dTTP, allowing for the continued synthesis of DNA. Dipyridamole, an inhibitor of nucleotide transport, prevents the replenishment of the intracellular pool of thymidine and thus enhances the cytotoxic effects of FU by interfering with the nucleoside salvage pathway.16,17 In vitro, a synergistic effect on cell kill was seen when cells were exposed to mitomycin for 4 hours, followed by continuous exposure to FU for 7 days.18 When added to infusional FU, mitomycin resulted in an improved failure-free survival, higher response rate, and better quality of life when compared with FU alone in the treatment of patients with colon cancer.19 On the basis of those preclinical findings, Isacoff et al20 initially tested the efficacy of FU administered as a protracted intravenous infusion in conjunction with leucovorin (LV), dipyridamole, and mitomycin in advanced colorectal cancer. Objective response was 61% with 10 complete responses. Subsequently, the same four-drug combination was tested in advanced pancreatic cancer.21 Of the 38 patients with locally advanced pancreatic cancer, 15 responded to therapy, for an overall response rate of 39%. The median survival was 15.5 months, with a 1-year survival rate of 70%. Four patients underwent a curative resection. These results formed the basis for testing this biochemically designed four-drug combination in a multi-institutional cooperative group setting (Southwest Oncology Group [SWOG] study S9700). The primary end point of this study was overall survival; secondary end points included time to progression and objective tumor response.
Patient Eligibility All patients provided written informed consent before enrollment onto the trial in accordance with the rules and regulations approved by the human subject protection committees. Patients were eligible if they had histologically or cytologically proven adenocarcinoma of the pancreas, with stage II or III disease that was not amenable to curative resection. Patients were excluded if they received any prior chemotherapy or radiation treatment for pancreatic cancer. Patients were required to be at least 2 weeks beyond surgical procedure. Patients with unresectable but localized disease were eligible if they had one of the following radiographic findings on computed tomography or magnetic resonance imaging: total occlusion or encasement of greater than 75% of the main portal vein or superior mesenteric vein; total occlusion or greater than 75% circumferential encasement of the superior mesenteric artery, celiac axis or common hepatic artery, or right or left hepatic arteries; total occlusion of the peripheral splenic vein in patients without evidence of cirrhosis; tumor size of greater than 5 cm involving the body or tail of the pancreas; or enlargement of the celiac nodes with subsequent biopsy to prove pathological involvement.
Patients could have either measurable or nonmeasurable disease. Measurable disease was defined by computed tomography or magnetic resonance imaging, and had to be bidimensionally measurable, with both diameters greater than the distance between the cuts of the imaging study. Patients were required to have a SWOG performance status of 0 to 2 with adequate hematologic, renal, and hepatic function as defined by an absolute neutrophil count of
Treatment Schedule Patients who underwent a curative pancreaticoduodenectomy resumed chemotherapy within 8 weeks after surgery and continued the treatment protocol until they received a total of 40 weeks of therapy including the presurgical treatment. Patients who underwent exploratory surgery but whose tumors were not amenable to curative resection resumed chemotherapy within 8 weeks of surgery and continued chemotherapy until there was evidence of disease progression. Patients with stable disease remained on treatment as per protocol at the discretion of the treating physician until they reached the criteria for resection, progression, or achieve a complete response (CR) or partial response (PR). Patients were removed from protocol treatment at the initial documentation of progression of disease, if they underwent curative surgery and completion of 40 weeks of therapy, if treatment was delayed more than 3 weeks due to toxicity, if unacceptable toxicity occurred, or if the patient wanted to discontinue treatment for any reason.
Patient Evaluation
Tumor response was categorized as a CR, PR, and stable/no response (SD) or disease progression. A CR is the complete disappearance of all measurable and assessable disease, with no new lesions or disease-related symptoms. A PR was defined as a Time to death was from the date of registration to the date of death as a result of any cause. Any patient who achieved a CR or PR at any time was re-evaluated for surgical resection. If a radiographic criterion for disease resectability was met, patients were then candidates for laparotomy with the intent of performing a curative pancreaticoduodenectomy.
Statistical Considerations
Patient Characteristics A total of 54 patients were entered onto study between November 1997 and June 2001. Four patients were deemed ineligible: three had stage 4 disease at baseline, and one never had the necessary baseline information submitted that was required to assess eligibility. Baseline characteristics of the 50 eligible patients are listed in Table 1. There were 27 males and 23 females. The median age of the patients was 61 years, with a median performance status of 1.
Primary End Point The primary end point of this study was overall survival. Of the 50 eligible patients, 27 survived past 1 year, for a 1-year survival probability of 54% (95% CI, 40% to 68%). The corresponding 2-year survival was 16% (95% CI, 6% to 26%). The median survival was 13.8 months (95% CI, 9.8 to 16.6 months).
Secondary End Points
Toxicity Grade 3 or 4 toxicity is listed in Table 3. In general, the treatment regimen was well tolerated. The most frequent toxicity was stomatitis, which occurred in 25% of patients, followed by diarrhea, and fatigue. Five patients experienced at least one grade 4 toxicity: one patient had dyspnea, one patient had increased serum bilirubin concentration, one patient had a perforated bowel, one patient had stomatitis, and one patient had both stomatitis and anemia. There were three documented cases of hemolytic uremic syndrome, all of which were treated successfully with plasma exchange with cryoprecipitate-poor plasma. Fourteen patients required hospitalization. There were four episodes of sepsis, two of which were associated with neutropenia. Other reasons for hospitalizations included biliary obstruction with fever, GI bleeding, and dehydration. There were no treatment-related deaths. One patient was hospitalized for congestive heart failure not believed to be related to treatment. Treatment was either withheld or modified in 20 and 11 patients, respectively. The most common reasons for modifying the dose of drugs was for stomatitis, followed by fatigue and weakness, hematologic toxicity, and hand-foot syndrome.
The goal of therapy for unresectable localized pancreas cancer is to delay locoregional disease progression and improve symptoms. However, a potential downsizing of an unresectable tumor will also give an opportunity for a radical resection that is the only chance for cure. The standard of care for such patients with localized disease is concurrent radiation with a fluoropyrimidine or other radiosensitizing agents.22 However, only few patients with unresected but localized cancer die because of the tumor in the pancreas. The majority of patients will succumb to metastatic disease that frequently involves the liver and peritoneum. Radiation-sensitizing doses and schedules of chemotherapy offer inadequate control of the metastatic disease. Moreover, the intensity of chemotherapy, administered concurrently or after radiation may be limited by the radiation itself. Therefore, focus should be placed on maximizing the efficacy of systemic therapy, similar to what is being done in patients with overt metastatic disease. In most studies, the median survival of patients with locally advanced unresectable pancreas cancer remained less that 1 year, even with regimens that included the newer generation of cytotoxic agents, such as gemcitabine and oxaliplatin.23 The biochemical rationale for developing the combination regimen of FU, LV, mitomycin, and dipyridamole was to overcome early drug resistance that is a major cause for treatment failure in pancreas cancer. Combination of agents with different biochemical profiles will delay disease progression and improve tumor control. Moreover, inclusion of dipyridamole to enhance the cytotoxicity of FU will enhance tumor-cell kill. This multi-institutional SWOG-wide trial demonstrated that the use of modulated infusional FU plus mitomycin was both a safe and effective treatment for patients with locally advanced pancreatic cancer. In this phase II trial the median survival of 13.8 months compared favorably with other studies that have also incorporated radiation therapy. Half of the patients were alive at 1 year. The treatment regimen was associated with moderate but acceptable toxicity. The adverse effects were predicted; most of the grade 3 or 4 toxicity was limited to stomatitis. There were no drug-related fatalities. Substitution of mitomycin by a different alkylating agent or a platinum agent to avoid hemolytic uremic syndrome would be a reasonable approach to develop this regimen further. The proper end point to design phase II exploratory trials in localized disease ranges from objective response assessment, conversion to resectability, to overall survival. Although objective response may not be a good surrogate for survival, tumor downsizing may provide the chance for a curative resection. Overall survival was selected as the primary end point because of the expected low rate of conversion to resectability and the clinical usefulness of survival improvement. The latter is also directly related to frequency of conversion to resectability. In this study, tumors in six of the responding patients met the radiographic criteria of resectability, all of which were resected successfully. Few studies have reported successful conversion to resectability. The Eastern Cooperative Oncology Group conducted a trial of preoperative FU plus mitomycin administered in conjunction with radiation followed by surgery.24 The median survival was 10.9 months. It was concluded that the poor outcome was related to the lack of effective systemic control of disease. Other studies have used more prolonged systemic combination therapies. Kamthan et al25 treated 35 patients with locally advanced stage II and III pancreatic adenocarcinoma with two or three induction cycles of chemotherapy that consisted of FU by continuous infusion for 4.5 days, streptozocin, and cisplatin. Radiation (54 Gy) was administered during the first and second chemotherapy cycle. Fifteen patients (42.8%) had objective responses to treatment. Nine of the responding patients underwent surgical exploration; five of these patients underwent complete surgical resection of tumor. The median survival was 15 months, with 1- and 2-year survival rates of 60% and 26%, respectively. Todd et al21 treated 38 patients with locally advanced adenocarcinoma of the pancreas with the same four-drug combination as used in our study. Patients received uninterrupted therapy until disease progression or unacceptable toxicity. The overall response rate was 39%. The median survival was 15.5 months and the 1-year survival rate was 70%. Four patients underwent successful pancreaticoduodenectomies. Results of those phase II trials suggest an improvement in outcome when more effective systemic therapies are used in localized pancreas cancer, with or without radiation therapy. However, no study thus far has shown a convincing benefit or lack of benefit for radiation therapy in this situation. It is likely that the benefit of radiation is limited to patients with truly localized disease with the least chance of systemic micrometastases at the time of initiation of therapy. In conclusion, this trial represents a unique experience in patients with locally advanced pancreatic cancer, in that the treatment regimen was entirely systemic and rationally developed based on biochemical criteria. A 13.8-month median survival compares favorably with the commonly used combined-modality approaches of FU and radiation. Finally, only a randomized study can answer the question definitely about whether a combination chemotherapy regimen is superior to the traditional fluoropyrimidine and concurrent radiation therapy in patients with locally advanced pancreas cancer. The impact of radiation therapy on the survival of patients with localized unresectable pancreas cancer remains to be determined and is the subject of ongoing research.
The authors indicated no potential conflicts of interest.
Conception and design: William H. Isacoff, Jacqueline K. Bendetti Administrative support: Jacqueline K. Bendetti, Philip A. Philip Provision of study materials or patients: William H. Isacoff, John J. Barstis, Abdul-Rahman Jazieh, John S. Macdonald, Philip A. Philip Collection and assembly of data: Jacqueline K. Bendetti, John J. Barstis, Abdul-Rahman Jazieh, John S. Macdonald, Philip A. Philip Data analysis and interpretation: William H. Isacoff, Jacqueline K. Bendetti, Philip A. Philip Manuscript writing: William H. Isacoff, Jacqueline K. Bendetti, John J. Barstis, Abdul-Rahman Jazieh, John S. Macdonald, Philip A. Philip Final approval of manuscript: Philip A. Philip
Supported in part by the following Public Health Service cooperative agreement grants by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA58348, CA76429, CA45450, CA58723, CA67575, CA46441, CA63844, CA37981, CA12644, CA46113, CA20319, CA35431, CA04919, CA16385, CA45560, CA35996, CA22433, CA35119, and CA58861. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Grem JL: 5-Fluorouracil plus leucovorin in cancer therapy. In De Vita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology, Vol 2 (ed 2). Philadelphia, PA, JP Lippincott, 1988, pp 1-13 11. Chabner BA (ed): Pyrimidine Antagonists in Pharmacologic Principles of Cancer Treatment. Philadelphia, PA, WB Saunders, 1982, pp 183-212 12. Aschele C, Sobrero A, Faderan MA, et al: Novel mechanisms of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 52:1855-1864, 1992 13. Sobrero FA, Aschele C, Bertino JR: Fluorouracil in colorectal cancer: A tale of two drugs—implications for biochemical modulation. J Clin Oncol 15:368-381, 1997 14. Grothey A, Descher B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU) folinic acid (FA) (MAYO) vs. weekly high dose 5-FU infusion/FA plus oxaliplatin (OXA) (FU FOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 21:129a, 2002 (suppl; abstr 512) 15. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 16. Van Mouwerik TJ, Pangallo CA, Willson JK, et al: Augmentation of methotrexate cytotoxicity in human colon cancer cells achieved through inhibition of thymidine salvage by dipyridamole. Biochem Pharmacol 36:809-814, 1987[CrossRef][Medline] 17. Grem JL: Biochemical modulation of fluorouracil by dipyridamole: Principal and clinical experience. Semin Oncol 19:56-65, 1992[Medline] 18. Russello O, Romanini A, Civallen S, et al: Time-dependent interactions between 5-fluorouracil and mitomycin-C on a human colon carcinoma cell line, HCT-8 in vitro. Eur J Cancer Clin Oncol 25:571-572, 1989[CrossRef][Medline] 19. Ross P, Cunningham D, Webb A, et al: A prospective randomized trial of protracted venous infusion 5-fluorouracil with or without mitomycin-C in advanced colorectal cancer. Ann Oncol 8:995-1001, 1997 20. Isacoff WH, Jacobs AD, Tylor O: Continuous infusion (CI) fluorouracil (5-FU) combined with calcium leucovorin, mitocycin-C (MMC), and dipyridomile (D) in advanced colorectal carcinoma. Proc Am Soc Clin Oncol 10:154, 1991 21. Todd KE, Gloor B, Lane JS, et al: Resection of locally advanced pancreatic cancer after down-staging with continuous-infusion 5-fluorouracil, mitomycin-C, leucovorin and dipyridamole. J Gastrointest Surg 2:159-166, 1998[CrossRef][Medline] 22. Tsai Ty, Innitti DA, Safran H: Combined modality therapy for pancreatic cancer. Semin Oncol 30:71-79, 2003[CrossRef][Medline] 23. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509-3516, 2005 24. Hoffman JP, Lipsitz S, Pisansky T: Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized resectable adenocarcinoma of the pancreas: An Eastern Cooperative Oncology Group Study. J Clin Oncol 16:317-323, 1998 25. Kamthan AG, Morris JC, Dalton T, et al: Combined modality therapy for stage II and stage III pancreatic cancer. J Clin Oncol 15:2920-2927, 1997[Abstract] Submitted March 24, 2006; accepted August 11, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1,500/mL, platelet count of 
2 mg/dL, bilirubin of 
